WO2002081661A2 - Combinaisons immunotherapeutiques utilisees dans le traitement de tumeurs surexprimant les gangliosides - Google Patents

Combinaisons immunotherapeutiques utilisees dans le traitement de tumeurs surexprimant les gangliosides Download PDF

Info

Publication number
WO2002081661A2
WO2002081661A2 PCT/CU2002/000002 CU0200002W WO02081661A2 WO 2002081661 A2 WO2002081661 A2 WO 2002081661A2 CU 0200002 W CU0200002 W CU 0200002W WO 02081661 A2 WO02081661 A2 WO 02081661A2
Authority
WO
WIPO (PCT)
Prior art keywords
ganglioside
antibody
vaccines
mab
gangliosides
Prior art date
Application number
PCT/CU2002/000002
Other languages
English (en)
Spanish (es)
Other versions
WO2002081661A3 (fr
Inventor
Luis Enrique FERNÁNDEZ MOLINA
Ana María VÁZQUEZ LÓPEZ
Rolando Pérez Rodríguez
Alexis Pérez González
Adriana CARR PÉREZ
Yildian Díaz Rodríguez
Mauro A ALFONSO FERNÁNDEZ
Adriana María ROJAS DEL CALVO
Original Assignee
Centro De Inmunologia Molecular
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to KR1020037012938A priority Critical patent/KR100863509B1/ko
Priority to MXPA03008738A priority patent/MXPA03008738A/es
Priority to AU2002308347A priority patent/AU2002308347B2/en
Priority to DE60228561T priority patent/DE60228561D1/de
Priority to EA200301097A priority patent/EA006936B1/ru
Priority to US10/473,978 priority patent/US20050069535A1/en
Priority to BR0208675-1A priority patent/BR0208675A/pt
Priority to NZ528598A priority patent/NZ528598A/en
Priority to DK02759751T priority patent/DK1384726T3/da
Priority to SI200230766T priority patent/SI1384726T1/sl
Priority to HU0401355A priority patent/HU228106B1/hu
Priority to CA2443372A priority patent/CA2443372C/fr
Priority to BRPI0208675-1A priority patent/BRPI0208675B1/pt
Priority to SK1216-2003A priority patent/SK287783B6/sk
Application filed by Centro De Inmunologia Molecular filed Critical Centro De Inmunologia Molecular
Priority to EP02759751A priority patent/EP1384726B1/fr
Priority to IL15824602A priority patent/IL158246A0/xx
Priority to JP2002580025A priority patent/JP4366080B2/ja
Priority to UA2003108988A priority patent/UA76745C2/uk
Publication of WO2002081661A2 publication Critical patent/WO2002081661A2/fr
Publication of WO2002081661A3 publication Critical patent/WO2002081661A3/fr
Priority to IS6964A priority patent/IS2701B/is
Priority to ZA2003/07679A priority patent/ZA200307679B/en
Priority to IL158246A priority patent/IL158246A/en
Priority to BG108227A priority patent/BG66293B1/en
Priority to NO20034436A priority patent/NO331533B1/no
Priority to HR20030806A priority patent/HRP20030806B1/xx
Priority to HK04109894A priority patent/HK1066818A1/xx

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/739—Lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001169—Tumor associated carbohydrates
    • A61K39/001171—Gangliosides, e.g. GM2, GD2 or GD3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39566—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against immunoglobulins, e.g. anti-idiotypic antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3076—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3076—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
    • C07K16/3084—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated gangliosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C07K16/4258—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig
    • C07K16/4266—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig against anti-tumor receptor Ig
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0693—Tumour cells; Cancer cells
    • C12N5/0694—Cells of blood, e.g. leukemia cells, myeloma cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • G01N33/686—Anti-idiotype
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • C12N5/12—Fused cells, e.g. hybridomas
    • C12N5/16—Animal cells
    • C12N5/163—Animal cells one of the fusion partners being a B or a T lymphocyte
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7023—(Hyper)proliferation
    • G01N2800/7028—Cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast

Definitions

  • the present invention relates to human medicine, specifically to therapeutic vaccines that induce an immune response against tumors that overexpress gangliosides.
  • Gangliosides are normal components of the plasma membranes of most mammalian cells. Although these glycosphingolipids are expressed in normal tissues, they are very attractive targets for immunotherapy due to the changes that occur in their expression patterns during the oncogenic transformation of cells (Hakomori, S. Ann. Rev. Biochem. 50; 1981: 733-764; Hakomori, Cancer Res. 45; 1985: 2405-2414; Irie RF, et al. In: Therapeutic monoclonal antibodies. Borrebaeck CAK, and Larrick JW (Eds.) M Stockton Press, 1990, pp. 75- 94).
  • Gangliosides are very poorly immunogenic both because they are their own antigens and because of their saccharide nature.
  • Some strategies, which have been explored to increase the immunogenicity of these antigens, are based on their presentation to the immune system in a different molecular environment.
  • One of these strategies has been the use of conjugated vaccines consisting of the covalent binding of the saccharide antigen to highly immunogenic dependent T-transport proteins, which has allowed obtaining a relatively long-lasting antibody response against certain gangliosides and the generation of IgG antibodies.
  • the titres of this antibody response after re-immunizations were lower compared to those obtained in response to classic independent thymus antigens (Helling, F et al. Cancer Res. 54; 1994: 197-203; Helling, F et al Cancer Res. 55; 1995: 2783-2788; Livingston PO et al. Cancer Immunol lmmunother 45; 1997: 10-19)
  • Novel vaccine compositions have been reported to induce an immune response against N-acetylated and N-glycolylated gangliosides.
  • These vaccines are based on the hydrophobic conjugation of gangliosides with very small proteoliposomes (VSSP) made up of the Neisseria meningitidis outer membrane protein complex (gangliosides / VSSP) (Estévez F. Y col. Vaccine 18; 1999: 190-197; US Patents 5,788,985 and US 6,149,921).
  • VSSP very small proteoliposomes
  • Vaccines consisting of GM3 / VSSP ganglioside or N-glycolyl GM3 ganglioside (NeuGcGM3) / VSSP have been shown to consistently produce high titers of specific IgM and IgG antibodies against GM3 and NeuGcGM3.
  • Administration of the GM3 / VSSP vaccine significantly increases the survival of mice carrying B16 melanoma, decreases tumor volumes and increases the ability to reject subcutaneous implantation of this tumor (Alonso et al. Int. J Oncology 15; 1999: 59-66; Carr A. et al. Melanoma Research (accepted for The idiotypic network theory proposed by Jeme 1974 (Jeme, NK Ann. Immunol.
  • Another alternative idea to induce antibodies against gangliosides that involves the use of Ab2 antibodies is the strategy that exploits the possibility that an epitope of saccharide nature can be represented by a protein epitope in the antibody molecule, making it more immunogenic.
  • anti-ld antibodies that mimic highly expressed gangliosides in tumor cells such as GM3, GD3, and GD2 have been obtained (Yamamoto, S et al. J. Nati. Cancer Inst 82; 1990: 1757-1760; Chapman, PB et al J. Clin Invest 88; 1991: 186-192; Cheung NK V, et al Int J Cancer 54; 1993: 499-505; Saleh MN. et al.
  • a mAb called P3 (with ECACC Deposit Number 94113026) is known, which has the particular characteristic of specifically recognizing N-glycolylated sialic acid in monosialo- and disialogangliosides.
  • This mAb Ab1 recognizes antigens present in human melanoma and breast tumors.
  • a gamma-type anti-idiotype mAb (not internal image) was obtained from mAb P3, identified as 1 E10 (ECACC Deposit Number 97112901), capable of producing an anti-tumor effect against murine breast and melanoma tumors (US Patent 6,063,379; Vázquez et al Hybridoma 14; 1995: 183-186; Vázquez et al Oncology Reports 7; 2000: 751 -756).
  • the present invention describes a pharmaceutical composition, or combination of pharmaceutical compositions, for immunotherapy of tumors that overexpress gangliosides, and that contains at least two of the components mentioned below:
  • A An idiotypic vaccine whose active ingredient is an anti-ganglioside antibody (Ab1);
  • a vaccine whose active ingredient is a ganglioside is a ganglioside.
  • Said pharmaceutical composition, or combination of pharmaceutical compositions may contain A and B, or A and C, or B and C.
  • the invention relates to that pharmaceutical composition, or combination of pharmaceutical compositions, where A can be an idiotypic vaccine whose active ingredient is the deposited murine anti-ganglioside antibody P3 with ECACC Deposit Number 94113026; and where B can be a idiotypic vaccine whose active ingredient is the murine anti-idiotype antibody E10 deposited with Deposit Number ECACC 97112901 and where C can be a vaccine whose active ingredient is the N-glycolyl GM3 gangliosides (NeuGcGM3) or N- acetyl GM3 (NeuAcGM3).
  • a and B, or A and C, or B and C are administered simultaneously or alternately.
  • the pharmaceutical composition, or combination of pharmaceutical compositions described in the present invention can be used for the treatment of tumors that overexpress gangliosides.
  • tumors that overexpress gangliosides.
  • gangliosides Preferably in the treatment of cancer of the breast, lung, digestive system, urogenital system, melanomas, sarcomas and tumors of neuroectodermal origin.
  • Also disclosed in the present invention is a method comprising administering the pharmaceutical composition, or combination of pharmaceutical compositions described above, to mammals for the prevention or treatment of breast, lung, digestive system, urogenital system, melanomas, sarcomas, and tumors. of neuroectodermal origin.
  • gangliosides as antigen are carried out as described by Estévez et al in Vacccine 18, 1999: 190-197 and in US Patents 5,788,985 and US 6,149,921, where natural or synthetic gangliosides are used as proteoliposome components made up of the protein complex of the outer membrane of Neisseria meningitidis (VSSP-G). These gangliosides could be (NeuGcGM), GD3 or (NeuAcGM). 2. Preparation of idiotypic vaccines:
  • compositions are prepared as described in US Patents 5,817,513 and US 6,063,379, where said vaccines contain murine anti-ganglioside monoclonal antibodies (mAbs) such as mAb P3 (ECACC Deposit Number 94113026) or mAbs.
  • mAbs murine anti-ganglioside monoclonal antibodies
  • Murine anti-idiotypes such as mAb 1 E10 (ECACC Repository Number 97112901) that recognize monoclonal anti-ganglioside antibodies. 3.
  • Immunotherapeutic combinations that cause potentiation of the immune response and the anti-tumor effect between vaccines containing gangliosides and idiotypic vaccines, or between the latter, in animal models:
  • the referred procedures can be used in mice or other species of mammals, being able to include all the variants of combinations of the different components mentioned above.
  • Animals are immunized with 3 to 10 doses ranging from 25 ⁇ g to 1 mg of murine ganglioside-recognizing mAb, with a dose interval ranging from 7 to 14 days. During this immunization period animals receive between 3 to 10 doses in a range between 60 to 1000 ⁇ g of the ganglioside-containing vaccine, with a time interval between doses of 7 to 14 days.
  • Another immunotherapeutic combination is in which animals receive between 3 to 10 doses in a range between 25 ⁇ g to 1 mg of a specific anti-idiotype mAb against an anti-ganglioside antibody, with a time between each dose that ranges from 7 to 14 days. During this immunization period, animals receive between 3 to 10 doses in a range between 60 to 1000 ⁇ g of the ganglioside-containing vaccine, with a time interval between doses of 7 to 14 days.
  • Vaccines can be formulated as separate products or within the same vaccine formulation for the situation in which they are supplied simultaneously. In case the administration is alternate, the animals receive the vaccines at intervals of 3-7 days between one type of vaccine and the other.
  • the vaccines are administered in an adjuvant that can be alumina (62.5 ⁇ g -2.5 mg), Montanide ISA 51 (0.1-1.2 ml / dose), or another appropriate one.
  • the total volume of a dose is 10 ⁇ l at 2 ml.
  • Vaccines containing the ganglioside (s) can be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intramucosally, or combinations thereof. Vaccines containing the antibodies can be administered by these same routes. The administration of said immunotherapeutic combinations in animals induces an increase in both the antibody response and the cellular immune response of the treated animals.
  • the size of the tumors, the tumor volume and survival of the treated animals are compared with groups of control animals, which were treated with each of the vaccines separately or with control preparations. After treatment with the aforementioned immunotherapeutic combinations in animals, a lower tumor incidence, a decrease in tumor growth and an increase in survival are observed, not only compared to the group treated only with the adjuvants, but with respect to the treated groups. with the different vaccines separately.
  • Immunotherapeutic combinations that potentiate the immune response and the anti-tumor effect between vaccines containing gangliosides and idiotypic vaccines, or between the latter, in patients:
  • the aforementioned procedures can be applied to patients in different clinical stages with tumors that overexpress gangliosides.
  • tumors of the digestive system the urogenital system, the lung, the breast, melanomas, sarcomas or of neuroectodermal origin.
  • the procedure consists of an induction phase where patients receive between 3 and 10 doses in a range between 0.1 to 5 mg of murine mAb that recognizes the ganglioside, with a time between each dose that will range from 7 to 14 days. These patients will receive during this phase between 3 to 10 doses in a range of 60 a. 1000 ⁇ g of the vaccine containing the ganglioside, with a time between each dose that will range from 7 to 14 days.
  • a second immunotherapeutic combination is in which patients are immunized with 3 to 10 doses ranging from 0.1 to 5 mg of a specific anti-idiotype mAb against an anti-ganglioside antibody, with a time between each dose ranging from 7 to 14 days.
  • a third immunotherapeutic combination is in which patients are immunized with murine mAb that recognizes ganglioside, with the same doses, frequency and intervals mentioned above, and that during this period patients receive between 3 to 10 doses in a range between 0.1 to 2 mg of a specific anti-idiotype mAb against an anti-ganglioside mAb.
  • Vaccines can be formulated as independent products or within the same vaccine formulation for the case in which they are supplied simultaneously.
  • the vaccines are administered in an adjuvant that could be alumina (1-5 mg / dose), Montanide ISA 51 (0.6-1.2 ml / dose), or another appropriate one.
  • the total volume of a dose ranges from 10 ⁇ l to 2 ml.
  • the vaccine containing the ganglioside or gangliosides can be administered intradermally, subcutaneously, intramuscularly, intramucosally or other route.
  • Antibody-containing vaccines can be administered by these same routes.
  • blood samples are taken to measure blood biochemistry parameters and specific antibody titers.
  • Lymphocytes are also obtained from patients for studies of cellular immunity. These extractions are carried out with a frequency that can be from one week to three months.
  • a maintenance phase is performed where patients can receive re-immunizations of each of the vaccines at the aforementioned concentrations, at intervals between 1 -6 months, simultaneously or at different times, for a period of 1 to 2 years .
  • the administration of said immunotherapeutic combinations in patients induces an increase in both the antibody response and the cellular immune response, and have an impact on tumor growth.
  • Example 1 Induction of anti-idiotype (T2) and anti-anti-idiotype (T3) T cells activation, in the syngeneic model by immunization with the murine mAb P3.
  • lymphocytes obtained to proliferate in vitro were measured by adding concentrations to the cultures of 25-150 ⁇ g / mL of both the murine mAb P3 and its anti-idiotype mAb 1E10 (ECACC Deposit Number 97112901).
  • Murine mAbs of the same isotype as the aforementioned mAbs were taken as controls. Positive proliferation indices were considered equal to or greater than 3. Lymphocytes obtained after immunization of Balb / c mice with Mab P3 were shown to proliferate specifically in the presence of Mab P3, and no proliferation was observed when confronted with Mab murine A3 (IgM) (Alfonso M. Y col. Hybridoma 14; 1995: 209-216).
  • IgM Mab murine A3
  • Example 2 Induction of anti-idiotype (T2) and anti-anti-idiotype (T3) T cells activation in mice by immunization with the chimeric P3 antibody.
  • the chimeric P3 antibody whose amino acid sequences of its heavy chain (VH) and light chain (VL) variable regions are shown in Figures 8 and 9 respectively, was used to immunize Balb / c female mice, 6-8 weeks old old.
  • 100 ⁇ g of the antibody emulsified in ACF were used subcutaneously, followed by re-immunization with 50 ⁇ g of the antibody emulsified in AIF seven days later.
  • the lymph nodes were collected and the lymphoproliferative capacity of these cells was measured by adding to the cultures: the chimeric P3 antibody, the chimeric E10 antibody 1, whose sequences of the variable regions are shown in Figures 13 and 14 , the murine mAb P3 and the murine mAb 1E10.
  • the murine mAb C5 Patent Application WO 97/33916 A1
  • the lymphocytes of mice immunized with the chimeric P3 antibody specifically proliferated when cultured in the presence of this chimeric antibody, as well as in the presence of the chimeric mAb 1 E10 and its murine varianrtes, and not against the antibodies used as isotype controls . Demonstrating that the chimeric P3 antibody maintains the ability to induce a specific proliferation of anti-idiotype (T2) and anti-anti-idiotypic T cells (T3) ( Figure 2).
  • Example 3 Enhancement of the anti-tumor effect produced by the GM3-VSSP / Montanide ISA 51 vaccine by the combination with the vaccine composed of the murine mAb 1E10 adsorbed on alumina gel.
  • a group of 6-57 week old female C57BL / 6 mice were immunized subcutaneously with 50 ⁇ g of the murine mAb 1E10 adsorbed on alumina gel on days 0, 14, 28 and 42.
  • the mice were immunized intramuscularly with 120 ⁇ g of GM3-VSSP / Montanide ISA 51 on days 7, 21, 35 and 49.
  • Another group of mice was similarly immunized, but initiating immunizations with the vaccine preparation containing the GM3 ganglioside.
  • Control groups immunized at the same time intervals and the same number of doses of each of the vaccines separately or immunized only with phosphate buffered saline were used in these experiments. All groups were inoculated with 10,000 murine B16 tumor cells subcutaneously on day 63. Tumor size was measured in all groups. For the statistical analysis of tumor size measurements, all groups were compared with respect to the control group that only received PBS using the Mixed Linear Model. Vaccination with mAb 1E10 did not protect against a 10,000 melanoma cell challenge B16. The VSSP-GM3 vaccine caused a delay in tumor growth (p ⁇ 0.05).
  • Antibody titers were measured by an ELISA assay, with OD values equal to or greater than 0.1 based on methanol being considered positive.
  • NeuGcGM-VSSP / Montanide ISA 51 vaccine toxicity consisted of erythema and local pain, induration at the injection site, fever. Light toxicity grade l / ll according to WHO criteria.
  • Example 5 Immunization scheme in cancer patients with the vaccine containing the anti-idiotype mAb 1E10 and using alumina gel as an adjuvant.
  • the administration of the vaccine preparation to the patients produced a slight toxicity, classified as grade I and II according to the WHO criteria.
  • a strong IgG-type Ab3 antibody response developed, detectable after receiving 2 6 3 doses of the vaccine preparation.
  • the analysis of the specificity of this response showed that the sera of all the patients had a higher recognition of the mAb 1 E10 than the rest of the mAbs of the same isotype used as controls, which suggested the induction of a specific response against the idiom of mAb 1 E10.
  • Example 6 Combination immunization scheme of the vaccine containing mAb 1 E10 and the NeuGcGM-VSSP vaccine.
  • Example 7 Recognition of tumor tissues by mAb 14F7.
  • MAb 14F7 has been shown to recognize NeuGcGM3 (patent WO9940119). The present example shows recognition results of this mAb from various human tumor locations.
  • Tissues were fixed in a 10% buffered formalin solution and dehydrated, clarified, and embedded in paraffin. Histopathology was evaluated in sections stained with hematoxylin eosin.
  • Consecutive cuts made from the blocks evaluated histologically were used to perform the immunolabelling by the streptavidin peroxidase biotin complex method previously described (Hsu, SM and Ralne, L. 1981.J Histochem Cytochem., 29: 1349-1353).
  • the deparaffinized and rehydrated sections were treated with 3% hydrogen peroxide (methanol solution) for 30 minutes, to eliminate endogenous peroxidase activity.
  • the sections were incubated with MaM 14F7 (purified) for 1 hour at room temperature. Subsequently, biotinylated anti-mouse serum and streptavidin peroxidase complex (Dakopatts) were added at room temperature.
  • the peroxidase reaction was revealed using 5 mL of a Tris-HCI buffered solution, 0.005 mL of 30% H 2 0 2, and 3 mg of 3-3 diaminobenzidine.
  • the sheets were washed with running water contrasted with Mayer's hematoxylin, coated with a mounting medium containing balsam and covered with coverslips. Reaction with the enzyme produces a carmelite-brown coloration.
  • Fresh biopsy fragments of pathological tissue were obtained within one hour of surgical excision. All the tissues were washed with saline solution, immediately frozen in liquid nitrogen and kept frozen at -80 ° C. The frozen fragments were cut in Leica cryostat at -25 ° C obtaining serial sections at 5 ⁇ m that were dried in air and they were used immediately or stored at -20 ° C wrapped in aluminum foil and post-fixed in 4% paraformaldehyde for 20 minutes.
  • TABLE II shows the immunohistochemical study of mAb 14F7 in new locations of human pathological tissues where a strong recognition in the membrane and cytoplasm of more than 50% of tumor cells is observed.
  • mice were immunized subcutaneously with 100 ⁇ g of the chimeric P3 antibody in ACF followed by re-immunization with 50 ⁇ g of the antibody emulsified in AIF. Three days later the lymph node cells were collected and the proliferation experiment was carried out in the presence of different concentrations of the different chimeric and murine antibodies.
  • FIG. 3 Kinetics of murine B16 tumor growth in mice immunized with the therapeutic combinations of the idiotypic vaccine containing the anti-idiotype mAb 1E10 and the GM3-VSSP vaccine, as detailed in Example 3.
  • Figure 4 Comparative study of metastatic skin lesions in a patient with melanoma. The photos were taken prior to immunization with the NeuGcGM / VSSP / ISA 51 vaccine, 2 and 4 months after treatment. Depigmented halos are seen around some of the lesions, stabilized lesions, lesions that decreased, and one lesion that increased in size.
  • Figure 5 Comparative study by Computerized Axial Tomography of the metastatic lesions in the right vertex of the lung, with a size of 18x20 mm in a patient with malignant melanoma, prior to immunization with the NeuGcGM / VSSP / ISA 51 vaccine and 4 months after the immunization. Stabilization of the lesion is observed.
  • Figure 6 Recognition of F (ab ') 2 fragments of mAb 1E10 and other mAbs of the same isotype by the sera of patients immunized with the idiotypic vaccine containing mAb 1 E10 and alumina gel as an adjuvant.
  • Figure 7 Recognition of the GM3 (NeuGc) (N-glycolylated) and GM3 (N-acetylated) gangliosides by the sera of the patients immunized with the idiotypic vaccine containing the mAb 1E10 and the alumina gel as an adjuvant.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Cell Biology (AREA)
  • Mycology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biotechnology (AREA)
  • Urology & Nephrology (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Engineering & Computer Science (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne le domaine de l'immunologie et, en particulier, des combinaisons immunothérapeutiques utilisées pour empêcher la croissance des cellules tumorales et/ou éliminer lesdites cellules. La présente invention permet d'observer un effet thérapeutique antitumoral par la combinaison de vaccins idiotypiques dont le principe actif est un anticorps antiganglioside (Ab1), avec des vaccins idiotypiques dont le principe actif est un anticorps anti-idiotype obtenu contre un anticorps antiganglioside (Ab2), ou avec des vaccins dont le principe actif est un ou plusieurs gangliosides. L'invention concerne des combinaisons de ces vaccins qui provoquent un synergisme de l'effet anti-tumoral induit séparément par chacun des vaccins. Lesdites combinaisons peuvent s'appliquer à des patients à différents stades cliniques de tumeurs surexprimant les gangliosides.
PCT/CU2002/000002 2001-04-06 2002-04-08 Combinaisons immunotherapeutiques utilisees dans le traitement de tumeurs surexprimant les gangliosides WO2002081661A2 (fr)

Priority Applications (25)

Application Number Priority Date Filing Date Title
BRPI0208675-1A BRPI0208675B1 (pt) 2001-04-06 2002-04-08 Combinação imunoterapêutica para a imunoterapia de tumores que superexpressam gangliosídeos, uso da mesma, e, uso de um método para controlar o crescimento e/ou a proliferação de tumores que superexpressam gangliosídeos
AU2002308347A AU2002308347B2 (en) 2001-04-06 2002-04-08 Immunotherapeutic combinations for the treatment of tumours that overexpress gangliosides
DE60228561T DE60228561D1 (de) 2001-04-06 2002-04-08 Immunotherapeutische kombinationen zur behandlung von tumoren, die ganglioside überexprimieren
EA200301097A EA006936B1 (ru) 2001-04-06 2002-04-08 Иммунотерапевтические комбинации для лечения опухолей, которые сверхэкспрессируют ганглиозиды
US10/473,978 US20050069535A1 (en) 2001-04-06 2002-04-08 Immunotherapeutic combinations for the treatment of tumours that overexpress gangliosides
BR0208675-1A BR0208675A (pt) 2001-04-06 2002-04-08 Combinação imunoterapêutica para a imunoterapaia de tumores que superexpressam gangliosìdeos, uso da mesma e método para controlar o crescimento e/ou a proliferação de células tumorais que superexpressam gangliosìdeos
NZ528598A NZ528598A (en) 2001-04-06 2002-04-08 Immunotherapeutic combinations for the treatment of tumours that overexpress gangliosides
DK02759751T DK1384726T3 (da) 2001-04-06 2002-04-08 Immunoterapeutiske kombinationer til behandling af tumorer, der overudtrykker gangliosider
SI200230766T SI1384726T1 (sl) 2001-04-06 2002-04-08 Imunoterapevtske kombinacije za zdravljenje tumorjev, ki ÄŤezmerno izraĹľajo gangliozide
HU0401355A HU228106B1 (en) 2001-04-06 2002-04-08 Immunotherapeutic combinations for the treatment of tumours that overexpress gangliosides
MXPA03008738A MXPA03008738A (es) 2001-04-06 2002-04-08 Combinaciones inmunoterapeuticas para el tratamiento de tumores que sobre-expresan glangliosidos.
SK1216-2003A SK287783B6 (sk) 2001-04-06 2002-04-08 Imunoterapeutická kombinácia na imunoterapiu nádorov, ktoré nadmerne exprimujú gangliozidy, a jej použitie
CA2443372A CA2443372C (fr) 2001-04-06 2002-04-08 Combinaisons immunotherapeutiques pour le traitement de tumeurs surexprimant les gangliosides
KR1020037012938A KR100863509B1 (ko) 2001-04-06 2002-04-08 강글리오사이드를 과발현하는 종양의 치료용 면역치료 조합
EP02759751A EP1384726B1 (fr) 2001-04-06 2002-04-08 Combinaisons immunotherapeutiques utilisees dans le traitement de tumeurs surexprimant les gangliosides
IL15824602A IL158246A0 (en) 2001-04-06 2002-04-08 Immunotherapeutic combinations for the treatment of tumours that overexpress gangliosides
JP2002580025A JP4366080B2 (ja) 2001-04-06 2002-04-08 ガングリオシドを過剰発現する腫瘍を治療するための免疫併用療法
UA2003108988A UA76745C2 (uk) 2001-04-06 2002-08-04 Імунотерапевтичні комбінації для лікування пухлин, які надекспресують гангліозиди
IS6964A IS2701B (is) 2001-04-06 2003-09-23 Ónæmismeðferðarsamsetningar til meðhöndlunar á æxlum sem oftjá ganglíósíð
ZA2003/07679A ZA200307679B (en) 2001-04-06 2003-10-01 Immunotherapeutic combinations for the treatment of tumours that overexpress gangliosides
IL158246A IL158246A (en) 2001-04-06 2003-10-02 Pharmaceutical compositions for the treatment of tumours that overexpress gangliosides and uses thereof
BG108227A BG66293B1 (en) 2001-04-06 2003-10-03 Immunotherapeutic combinations for the treatment of tumours that overexpress gangliosides
NO20034436A NO331533B1 (no) 2001-04-06 2003-10-03 Immunoterapeutiske kombinasjoner for behandling av tumorer som overuttrykker gangliosider
HR20030806A HRP20030806B1 (en) 2001-04-06 2003-10-06 Immunotherapeutic combinations for the treatment of tumours that overexpress gangliosides
HK04109894A HK1066818A1 (fr) 2001-04-06 2004-12-14

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CU84/2001 2001-04-06
CU2001008420010084A CU23007A1 (es) 2001-04-06 2001-04-06 Combinaciones inmunoterapéuticas para el tratamiencombinaciones inmunoterapéuticas para el tratamiento de tumores que sobre-expresan gangliósidos to de tumores que sobre-expresan gangliósidos

Publications (2)

Publication Number Publication Date
WO2002081661A2 true WO2002081661A2 (fr) 2002-10-17
WO2002081661A3 WO2002081661A3 (fr) 2003-01-03

Family

ID=40291118

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CU2002/000003 WO2002081496A2 (fr) 2001-04-06 2002-04-08 Anticorps de recombinaison associes a des gangliosides et leur utilisation dans le diagnostic et le traitement des tumeurs
PCT/CU2002/000002 WO2002081661A2 (fr) 2001-04-06 2002-04-08 Combinaisons immunotherapeutiques utilisees dans le traitement de tumeurs surexprimant les gangliosides

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/CU2002/000003 WO2002081496A2 (fr) 2001-04-06 2002-04-08 Anticorps de recombinaison associes a des gangliosides et leur utilisation dans le diagnostic et le traitement des tumeurs

Country Status (37)

Country Link
US (3) US20050069535A1 (fr)
EP (3) EP1798243B1 (fr)
JP (2) JP4366080B2 (fr)
KR (3) KR100863509B1 (fr)
CN (3) CN101054417B (fr)
AR (2) AR033123A1 (fr)
AT (3) ATE477279T1 (fr)
AU (3) AU2002308348B2 (fr)
BG (2) BG66293B1 (fr)
BR (3) BR0208675A (fr)
CA (2) CA2443372C (fr)
CU (1) CU23007A1 (fr)
CZ (2) CZ304424B6 (fr)
DE (2) DE60228561D1 (fr)
DK (2) DK1384726T3 (fr)
EA (2) EA006936B1 (fr)
EC (2) ECSP034788A (fr)
ES (2) ES2296986T3 (fr)
HK (3) HK1066818A1 (fr)
HR (2) HRP20030805B1 (fr)
HU (2) HU228106B1 (fr)
IL (2) IL158246A0 (fr)
IS (2) IS2701B (fr)
MX (2) MXPA03008738A (fr)
MY (3) MY145703A (fr)
NO (2) NO331533B1 (fr)
NZ (2) NZ528599A (fr)
PE (1) PE20020972A1 (fr)
PL (2) PL371770A1 (fr)
PT (2) PT1384726E (fr)
SG (1) SG161737A1 (fr)
SI (2) SI1384726T1 (fr)
SK (2) SK287783B6 (fr)
UA (3) UA75393C2 (fr)
UY (2) UY27243A1 (fr)
WO (2) WO2002081496A2 (fr)
ZA (2) ZA200307585B (fr)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7297336B2 (en) * 2003-09-12 2007-11-20 Baxter International Inc. Factor IXa specific antibodies displaying factor VIIIa like activity
RU2396088C2 (ru) * 2005-02-04 2010-08-10 СУРВАК АпС Вакцина на основе пептидов сурвивина
FI20055398A0 (fi) * 2005-07-08 2005-07-08 Suomen Punainen Risti Veripalv Menetelmä solupopulaatioiden evaluoimiseksi
CA2618796C (fr) * 2005-08-11 2018-01-02 Arpi Matossian-Rogers Peptides pour traitement et diagnostic d'une maladie auto-immune
WO2007024535A2 (fr) 2005-08-19 2007-03-01 Wyeth Anticorps antagonistes contre gdf-8 et utilisations pour le traitement de als et d'autres troubles associes a gdf-8
ITFI20060163A1 (it) * 2006-06-29 2006-09-28 Menarini Internat Operations Luxembourg Sa Composizione farmaceutica contenente un anticorpo monoclonale anti idiotipico anti-ca-125 ed alluminio
TWI434855B (zh) 2006-11-21 2014-04-21 Hoffmann La Roche 結合物及其在免疫分析中作為參考標準之用途
US20110286937A1 (en) * 2008-02-22 2011-11-24 Gifu University Synthetic glycolipid-containing liposome
EP2166085A1 (fr) 2008-07-16 2010-03-24 Suomen Punainen Risti Veripalvelu Cellules modifiées bivalentes
TWI516501B (zh) 2008-09-12 2016-01-11 禮納特神經系統科學公司 Ｐｃｓｋ９拮抗劑類
NZ612647A (en) 2009-03-10 2015-03-27 Biogen Idec Inc Anti-bcma antibodies
JP6132548B2 (ja) * 2009-04-01 2017-05-24 ジェネンテック， インコーポレイテッド 抗ＦｃＲＨ５抗体および免疫接合体および使用方法
CU23736A1 (es) 2009-05-04 2011-11-15 Centro Inmunologia Molecular Anticuerpos que reconocen sulfatidos y proteoglicanos sulfatados y su uso
WO2011026242A1 (fr) * 2009-09-03 2011-03-10 Vancouver Biotech Ltd. Anticorps monoclonaux dirigés contre le récepteur de l'hormone de libération des gonadotrophines
AU2012205663B2 (en) * 2011-01-10 2017-02-02 Emory University Antibodies directed against influenza
CU24070B1 (es) 2011-12-27 2015-01-29 Ct De Inmunología Molecular Composiciones farmacéuticas para el tratamiento de tumores que expresan regf y gangliósidos n-glicolilados gm3 (neugcgm3)
EP2641916A1 (fr) * 2012-03-23 2013-09-25 Centre National de la Recherche Scientifique (C.N.R.S) Nouveaux anticorps anti sPLA2-IIA et leurs utilisations
WO2013186719A1 (fr) 2012-06-15 2013-12-19 Pfizer Inc. Anticorps antagonistes améliorés dirigés contre gdf-8 et leurs utilisations
TWI725931B (zh) 2013-06-24 2021-05-01 美商建南德克公司 抗ｆｃｒｈ５抗體
PE20210107A1 (es) 2013-12-17 2021-01-19 Genentech Inc Anticuerpos anti-cd3 y metodos de uso
JP2017512759A (ja) * 2014-04-10 2017-05-25 オービーアイ ファーマ インコーポレイテッド 抗体、前記抗体を産生するハイブリドーマ、前記抗体を含む薬学的組成物及びその用途
TWI715587B (zh) 2015-05-28 2021-01-11 美商安可美德藥物股份有限公司 Ｔｉｇｉｔ結合劑和彼之用途
IL256079B2 (en) 2015-06-16 2024-01-01 Genentech Inc Human antibodies with improved affinity to FCRH5 - and methods of use
WO2018017864A2 (fr) * 2016-07-20 2018-01-25 Oncomed Pharmaceuticals, Inc. Agents de liaison à pvrig et leurs utilisations
RU2765410C2 (ru) 2016-11-30 2022-01-28 Онкомед Фармасьютикалс, Инк. Способы лечения рака, включающие связывающие tigit агенты
CU20170173A7 (es) * 2017-12-27 2019-11-04 Ct Inmunologia Molecular Nano-partículas que contienen el gangliósido gm3 como inmunomoduladoras

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0586002A2 (fr) * 1992-08-18 1994-03-09 CENTRO de IMMUNOLOGIA MOLECULAR Anticorps monoclonaux contre le récepteur du facteur épidermique de croissance, cellules et méthodes pour leur préparation et compositions qui les contiennent
EP0657471A1 (fr) * 1993-12-09 1995-06-14 Centro de Inmunologia Molecular Anticorps monoclonaux contre des gangliosides et leurs utilisations dans l'immunothérapie active spécifique des tumeurs malignes
EP0661061A2 (fr) * 1993-12-29 1995-07-05 Centro de Inmunologia Molecular Vaccin capable de provoquer une réponse immunitaire contre les gangliosides-N-glycolylés et son application anti-cancéreuse
WO1999020656A1 (fr) * 1997-10-21 1999-04-29 Centro De Inmunologia Molecular (Cim) Anticorps monoclonaux anti-idiotypes, leur utilisation dans l'immunotherapie active de tumeurs malignes et compositions les renfermant
US6149921A (en) * 1993-12-29 2000-11-21 Centro De Inmunologia Molecular Vaccine compositions for eliciting an immune response against N-acetylated gangliosides and their use for cancer treatment

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2754206B2 (ja) * 1987-11-17 1998-05-20 メクト株式会社 α２→３結合を認識するモノクローナル抗体
US6051225A (en) * 1988-10-19 2000-04-18 The Dow Chemical Company Family of high affinity, modified antibodies for cancer treatment
JPH07101999A (ja) * 1993-10-06 1995-04-18 Hagiwara Yoshihide 抗癌ヒトモノクローナル抗体に対する抗イデイオタイプ抗体のアミノ酸配列およびそれをコードするｄｎａ塩基配列
US6063379A (en) * 1993-12-09 2000-05-16 Centro De Inmunologia Molecular Anti-idiotypic monoclonal antibodies and compositions including the anti-idiotypic monoclonal antibodies
CU22615A1 (es) * 1994-06-30 2000-02-10 Centro Inmunologia Molecular Procedimiento de obtención de anticuerpos monoclonales murinos menos inmunogénicos. anticuerpos monoclonales obtenidos
CU22731A1 (es) * 1998-02-05 2002-02-28 Centro Inmunologia Molecular Anticuerpo monoclonal que reconoce el oligosacárido ácido siálico n´glicolilado-galactosa-glucosa (ngcneu-gal-glu) en tumores malignos y composiciones farmacéuticas que los contienen
US7442776B2 (en) * 1999-10-08 2008-10-28 Young David S F Cancerous disease modifying antibodies

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0586002A2 (fr) * 1992-08-18 1994-03-09 CENTRO de IMMUNOLOGIA MOLECULAR Anticorps monoclonaux contre le récepteur du facteur épidermique de croissance, cellules et méthodes pour leur préparation et compositions qui les contiennent
EP0657471A1 (fr) * 1993-12-09 1995-06-14 Centro de Inmunologia Molecular Anticorps monoclonaux contre des gangliosides et leurs utilisations dans l'immunothérapie active spécifique des tumeurs malignes
EP0661061A2 (fr) * 1993-12-29 1995-07-05 Centro de Inmunologia Molecular Vaccin capable de provoquer une réponse immunitaire contre les gangliosides-N-glycolylés et son application anti-cancéreuse
US6149921A (en) * 1993-12-29 2000-11-21 Centro De Inmunologia Molecular Vaccine compositions for eliciting an immune response against N-acetylated gangliosides and their use for cancer treatment
WO1999020656A1 (fr) * 1997-10-21 1999-04-29 Centro De Inmunologia Molecular (Cim) Anticorps monoclonaux anti-idiotypes, leur utilisation dans l'immunotherapie active de tumeurs malignes et compositions les renfermant

Also Published As

Publication number Publication date
CN100349920C (zh) 2007-11-21
HUP0401355A3 (en) 2012-05-29
AU2002308347B2 (en) 2006-09-14
ATE378356T1 (de) 2007-11-15
ZA200307679B (en) 2005-03-30
CZ20032641A3 (cs) 2004-07-14
PL371770A1 (en) 2005-06-27
MXPA03008738A (es) 2003-12-11
CA2441845C (fr) 2011-06-07
ES2312610T3 (es) 2009-03-01
JP2004525953A (ja) 2004-08-26
IL158246A0 (en) 2004-05-12
EA006936B1 (ru) 2006-06-30
CA2443372A1 (fr) 2002-10-17
IL158246A (en) 2010-05-31
HK1109160A1 (en) 2008-05-30
AR033123A1 (es) 2003-12-03
AU2002308348B2 (en) 2007-11-22
CU23007A1 (es) 2004-12-17
IS2701B (is) 2010-11-15
BR0208675A (pt) 2004-08-03
EP1384726B1 (fr) 2008-08-27
BR0208676B1 (pt) 2017-11-14
ATE406386T1 (de) 2008-09-15
NO20034436L (no) 2003-12-02
US8758753B2 (en) 2014-06-24
UY27243A1 (es) 2002-09-30
BG66293B1 (en) 2013-02-28
NO20034437D0 (no) 2003-10-03
EP1384726A2 (fr) 2004-01-28
MY137078A (en) 2008-12-31
HRP20030805A2 (en) 2005-08-31
CA2443372C (fr) 2013-05-28
HRP20030806A2 (en) 2005-08-31
NO331533B1 (no) 2012-01-23
SI1384726T1 (sl) 2009-04-30
KR20030087053A (ko) 2003-11-12
HK1066818A1 (fr) 2005-04-01
PE20020972A1 (es) 2003-01-02
SK12262003A3 (sk) 2004-08-03
UA76745C2 (uk) 2006-09-15
EA200301098A1 (ru) 2004-04-29
PT1411064E (pt) 2008-02-12
US20100297008A1 (en) 2010-11-25
ECSP034787A (es) 2004-01-28
EP1411064B1 (fr) 2007-11-14
ATE477279T1 (de) 2010-08-15
KR20080080680A (ko) 2008-09-04
KR100863509B1 (ko) 2008-10-15
HK1070080A1 (en) 2005-06-10
DK1384726T3 (da) 2008-12-15
ES2296986T3 (es) 2008-05-01
PL371937A1 (en) 2005-07-11
SK287914B6 (sk) 2012-03-02
CZ296276B6 (cs) 2006-02-15
BG66304B1 (bg) 2013-03-29
HU228105B1 (en) 2012-11-28
WO2002081496A2 (fr) 2002-10-17
CN101054417A (zh) 2007-10-17
BG108227A (bg) 2005-04-30
PT1384726E (pt) 2008-12-05
MY157372A (en) 2016-06-15
IS6965A (is) 2003-09-23
EP1411064A2 (fr) 2004-04-21
CA2441845A1 (fr) 2002-10-17
BG108228A (bg) 2005-04-30
WO2002081661A3 (fr) 2003-01-03
CZ20032668A3 (cs) 2004-07-14
HUP0401695A3 (en) 2012-05-29
CN1507452A (zh) 2004-06-23
SG161737A1 (en) 2010-06-29
HUP0401355A2 (hu) 2004-10-28
JP4366080B2 (ja) 2009-11-18
EA006310B1 (ru) 2005-10-27
AR033122A1 (es) 2003-12-03
NO20034437L (no) 2003-12-02
ECSP034788A (es) 2004-01-28
CN101054417B (zh) 2012-07-11
AU2007231687B2 (en) 2010-09-30
HRP20030806B1 (en) 2011-11-30
CN1535282A (zh) 2004-10-06
UY27242A1 (es) 2002-07-31
US20050069535A1 (en) 2005-03-31
HRP20030805B1 (en) 2011-11-30
EP1798243A2 (fr) 2007-06-20
CN1319991C (zh) 2007-06-06
EP1798243A3 (fr) 2007-10-17
NZ528598A (en) 2005-03-24
IS6964A (is) 2003-09-23
MY145703A (en) 2012-03-30
DE60228561D1 (de) 2008-10-09
WO2002081496A3 (fr) 2004-02-19
KR20030092048A (ko) 2003-12-03
SI1411064T1 (sl) 2008-04-30
KR100919617B1 (ko) 2009-09-29
UA86768C2 (ru) 2009-05-25
EA200301097A1 (ru) 2004-02-26
CZ304424B6 (cs) 2014-04-30
SK287783B6 (sk) 2011-09-05
UA75393C2 (en) 2006-04-17
JP2004528033A (ja) 2004-09-16
NZ528599A (en) 2005-03-24
KR100946168B1 (ko) 2010-03-11
HUP0401695A2 (en) 2006-08-28
EP1798243B1 (fr) 2010-08-11
NO20034436D0 (no) 2003-10-03
PL208109B1 (pl) 2011-03-31
ZA200307585B (en) 2004-09-16
HU228106B1 (en) 2012-11-28
DE60223547T2 (de) 2008-09-18
MXPA03008739A (es) 2003-12-11
AU2007231687A1 (en) 2007-11-22
DK1411064T3 (da) 2008-03-25
BRPI0208675B1 (pt) 2018-03-13
US20040253233A1 (en) 2004-12-16
DE60223547D1 (de) 2007-12-27
SK12162003A3 (sk) 2004-05-04
BR0208676A (pt) 2008-04-08

Similar Documents

Publication Publication Date Title
WO2002081661A2 (fr) Combinaisons immunotherapeutiques utilisees dans le traitement de tumeurs surexprimant les gangliosides
ES2374845T3 (es) Tratamiento de cáncer con anticuerpos anti-il-1.
Mulens et al. Immunogenicity and safety of a NeuGcGM3 based cancer vaccine: Results from a controlled study in metastatic breast cancer patients.
ES2348312T3 (es) Vacuna her-2/neu a base de múltiples péptidos.
Fernández et al. Ganglioside-based vaccines and anti-idiotype antibodies for active immunotherapy against cancer
WO1999040119A1 (fr) Anticorps monoclonal reconnaissant l'oligosaccharide acide sialique n-glycolyle-galactose-glucose dans les tumeurs malignes et sa composition
Diaz et al. Anti-ganglioside anti-idiotypic monoclonal antibody-based cancer vaccine induces apoptosis and antiangiogenic effect in a metastatic lung carcinoma
WO2019086056A1 (fr) Nanoparticules contenant des variants synthétiques de la ganglioside gm3 en tant qu'adjuvants dans des vaccins
US20060246056A1 (en) Immunotherapy of rectal cancer
US20050169929A1 (en) Use of a vaccine for active immunization against cancer
ES2694324T3 (es) Composiciones farmacéuticas para el tratamiento de tumores que expresan el REGF y el gangliósido N-glicolil GM3 (NeuGcGM3)
ES2274584T3 (es) Anticuerpos monoclonales anti-idiotipicos, su uso en inmunoterapia activa de tumores malignos y composiciones que contienen los mismos.
enrique Fernandez Immunogenicity and safety of a NeuGcGM3 based cancer vaccine
JP2001055341A (ja) 免疫応答を惹起するための、多数エピトープ含有抗原の再構成法および組成物

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2443372

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/008738

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1550/DELNP/2003

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: PV2003-2641

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 03086747

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 2003/07679

Country of ref document: ZA

Ref document number: 528598

Country of ref document: NZ

Ref document number: 200307679

Country of ref document: ZA

Ref document number: 12162003

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: 158246

Country of ref document: IL

Ref document number: 1020037012938

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 10822702

Country of ref document: BG

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: P20030806A

Country of ref document: HR

Ref document number: 2002580025

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 028084330

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2002759751

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 200301097

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 2002308347

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2002759751

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2003-2641

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 10473978

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 528598

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 528598

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: PV2003-2641

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 2002759751

Country of ref document: EP